Two widely used systems for the administration of drugs to the airways are the dry powder inhalers (DPIs) comprising micronized drug particles as dry powder usually admixed with coarser excipient particles of pharmacologically inert materials such as lactose, and the pressurized metered-dose inhalers (pMDIs) which may comprise a suspension of micronized drug particles in a propellant gas. This present invention is relevant to both these methods of delivery.
Nasal delivery is a means to enable administration of drug particles to the central nervous system (CNS-nose to brain), systemic and topical nasal formulations whether as powders or of liquid suspension. Various breath activated devices deliver intranasal drugs to targeted regions of the nasal cavity, including the sinuses and the olfactory region, without lung deposition. This present invention is relevant to this method of delivery.
The control of crystal and precipitate particle size of active and other compositional ingredients is necessary in industries in which the final product form of the active ingredient of interest is in the form of a fine powder, such as in the pharmaceutical and agrochemical industries. The manner in which an active ingredient behaves in a biological system depends upon many factors inter alia the size of the particle and the crystal form. Small particles may be made by processes such as milling, but such processes may have a detrimental effect on the material properties of the milled particles. Furthermore, a significant proportion of particles may be produced which are of a shape that is unsuitable for a given end use. When particles are milled they may undergo morphological alterations, leading to undesirable surface polymorphological transformation which in turn may give rise to the formation of amorphous structures that are unsuitable for end purpose applications, such as in a pharmaceutical formulation designed for inhalation. In addition, milling generates considerable heat which may make particulate milling inappropriate, for example, where the active ingredient is a low melting solid. In addition, the physical performance of particles destined for use in aerosols may be compromised if they become highly charged as a result of milling.
Techniques for the production of drug particles may include the generation of an aerosol of droplets from a solution of the drug and subsequent spray drying of the droplets to solidify the particles. Spray drying is one of the most widely used of industrial processes involving particle formation and drying. It is highly suited for the continuous production of dry solids in either powder, granulate or agglomerate form from, for example, liquid feed stocks as solutions, emulsions or pumpable suspensions. Therefore, spray drying is an ideal process where the end-product should comply with quality standards regarding such parameters as particle size distribution, residual moisture content, bulk density, particle shape and the like. A disadvantage of conventional spray drying techniques is that the particles being dried tend to be in an amorphous form, perhaps as high as 100%, rather than in a crystalline particulate form, since solidification is typically rapid, and in addition the processing leads to a high degree of agglomeration of dried particulates. Freeze drying of aerosol droplets is also used in the art to obtain particles but again, the typically rapid solidification that occurs generally leads to the generation of amorphous particles.
WO 2004/073827 describes the preparation of particles in a process referred to as SAX, comprising the steps of forming a solution of a desired substance in a suitable solvent, generating an aerosol therefrom, collecting the aerosol droplets in a non-solvent for the said substance, and applying ultrasound to the droplets dispersed in the non-solvent to effect crystallisation of the substance. A disadvantage of this technique is the need to have a critical control over the degree of solvent evaporation from the aerosol.
Inhalation represents a very attractive, rapid and patient-friendly route for the delivery of systemically acting drugs, as well as for drugs that are designed to act locally on the lungs themselves, such as asthma, chronic obstructive pulmonary disease and infection. It is particularly desirable and advantageous to develop technologies for delivering drugs to the lungs in a predictable and reproducible manner. Drug inhalation benefits include rapid speed of onset; improved patient acceptance and compliance for a non-invasive systemic route; reduction of side effects; product life cycle extension; improved consistency of delivery; access to new forms of therapy, including higher doses, greater efficiency and accuracy of targeting.
Dry powder inhalation (DPI) plays an important role in the treatment of diseases of the lung. Primarily they were developed to overcome problems encountered using Metered Dose Inhalers (MDIs), and later, because they are propellant free and hence more environmental friendly. Using an MDI the patient has to coordinate inhalation and inhaler actuation so that the aerosol cloud can reach the lungs. Dry Powder inhalers (DPIs) are breath actuated, so that theoretically the aerosol cloud should reach the lungs without problems. However, problems arise due to technical limitations with respect to handling, content uniformity of dose and control of dose. Also, the inspiratory flow rate varies between patients and depends on the mechanical principle of the DPI. DPIs which reduce the inspiratory flow rate considerably due to a high flow resistance are less suitable, because the rate of lung deposition of an aerosol cloud depends on the inspiratory flow rate.
Powder technology, however, for successful dry powders and DPI products remains a significant technical hurdle. Formulations must have suitable flow properties, not only to assist in the manufacture and metering of the powders, but also to provide reliable and predictable resuspension and fluidisation, and to avoid excessive retention of the powder within the dispensing device. The drug particles or particles of pharmaceutically active material (also referred to herein as API particles) in the resuspended powder must aerosolise appropriately so that they can be transported to the appropriate target area within the lung. Typically, for lung deposition, the active particles have a diameter of less than 10 μm, frequently 0.1 to 7 μm or 0.1 to 5 μm.
In this kind of system the interaction between drug-to-drug and drug-to-carrier particles and particle-to-wall are of great importance for successful drug delivery to the deep lung. The interaction between particles is determined by adhesion forces such as van der Waals, capillary, and coulombic forces. The strength of these forces is affected by the particle size, shape, and morphology. Spherical or rounded particles with a rough surface are considered best for pulmonary drug delivery due to their small contact area and increased separation distance between particles. Large separation distance decreases the attachment forces and improves the powder dispersion. Particle engineering for the optimum drug particles together with DPI device engineering are essential for efficient drug delivery via the lungs. WO 2006056812 reports the invention concerned with a refinement of the processing of particles that are to form a dry powder formulation which is to be administered to the lung using a dry powder inhaler (DPI) device whereby the processing of particles of active material and particles of carrier material is carried out in the presence of additive material to provide a powder composition which exhibits excellent powder properties.
When dry powders are produced in conventional processes, the active particles will vary in size, and often this variation can be considerable. This can make it difficult to ensure that a high enough proportion of the active particles are of the appropriate size for administration to the correct site. It is therefore desirable to have a dry powder formulation wherein the size distribution of the active particles is as narrow as possible. For example, preferably the particle distribution is Gaussian, preferably the particle distribution is monomodal. Further, for example, the geometric standard deviation of the active particle aerodynamic or volumetric size distribution is preferably not more than 2, more preferably not more than 1.8, not more than 1.6, not more than 1.5, not more than 1.4, or even not more than 1.2. This will improve dose efficiency and reproducibility.
The Mass Median Aerodynamic Diameter (MMAD) is the particle diameter below which 50% of the particles enter an impactor suitable for determining in vitro performance of inhaled drug particles and takes account of both shape and density. A sample with a MMAD of (say) 5 μm will have 50 per cent of the total mass (i.e. not the total number) of particles with a diameter of more than 5 μm and 50 per cent with a diameter of less than 5 μm.
Fine particles, with an MMAD of less than 10 μm and smaller, tend to be increasingly thermodynamically unstable as their surface area to volume ratio increases, which provides an increasing surface free energy with this decreasing particle size, and consequently increases the tendency of particles to agglomerate and the strength of the agglomerate. In the inhaler, agglomeration of fine particles and adherence of such particles to the walls of the inhaler are problems that result in the fine particles leaving the inhaler as large, stable agglomerates, or being unable to leave the inhaler and remaining adhered to the interior of the inhaler, or even clogging or blocking the inhaler.
The uncertainty as to the extent of formation of stable agglomerates of the particles between each actuation of the inhaler, and also between different inhalers and different batches of particles, leads to poor dose reproducibility. Furthermore, the formation of agglomerates means that the MMAD of the active particles can be vastly increased, with agglomerates of the active particles not reaching the required part of the lung. These μm to sub μm particle sizes required for deep lung or systemic delivery lead to the problem that the respirable active particles tend to be highly cohesive, which means they generally exhibit poor flowability and poor aerosolisation.
To overcome the highly cohesive nature of such respirable active particles, formulators have, in the past, included larger carrier particles of an inert excipient in powder formulations, in order to aid both flowability and drug aerosolisation. These large carrier particles have a beneficial effect on the powder formulations because, rather than sticking to one another, the fine active particles tend to adhere to the surfaces of the larger carrier particles whilst in the inhaler device. The active particles are released from the carrier particle surfaces and become dispersed upon actuation of the dispensing device, to give a fine suspension which may be inhaled into the respiratory tract.
Whilst the addition of relatively large carrier particles does tend to improve the powder properties, it also has the effect of diluting the drug, usually to such an extent that 95% or more by total weight of the formulation is carrier. Relatively large amounts of carrier are required in order to have the desired effect on the powder properties because the majority of the fine or ultra-fine active particles need to adhere to the surfaces of the carrier particles, otherwise the cohesive nature of the active particles still dominates the powder and results in poor flowability. The surface area of the carrier particles available for the fine particles to adhere to decreases with increasing diameter of the carrier particles. However, the flow properties tend to become worse with decreasing diameter. Hence, there is a need to find a suitable balance in order to obtain a satisfactory carrier powder. An additional consideration is that one can get segregation if too few carrier particles are included, which is extremely undesirable.
An additional problem experienced by formulators is the variability in surface properties of drug and excipient particles. Each active agent powder has its own unique inherent stickiness or surface energy, which can range tremendously from compound to compound. Further, the nature of the surface energies can change for a given compound depending upon how it is processed. For example, jet milling is notorious for generating significant variations in surface properties because of the aggressive nature of the collisions it employs. Such variations can lead to increased surface energy and increased cohesiveness and adhesiveness. Even in highly regular, crystalline powders, the short range Lifshitz-van der Weals forces can lead to highly cohesive and adhesive powders.
If no carrier excipient is used, the micronized drug particles are loosely agglomerated via Lifshitz-van der Weals forces only. It is important for the function of such a formulation that no capillary forces are formed, because the particle agglomerates must be de-agglomerated in the air stream. Capillary forces are usually several times larger than, for example, Lifshitz-van der Weals forces, and the ability of such an agglomerate to be split into the single particles decreases with increasing autoadhesion forces holding the agglomerates together. Such a loose agglomeration can be achieved using a spheronisation process.
The forces acting on a particle adhered to a carrier particle when placed into an air stream can be described by lift force (the lift of smaller particle away from carrier particle; this can be neglected for micronized powders), the drag force (to compensate for adhesion and friction forces), the adhesion force and friction force (force preventing tangential displacement of two surfaces in contact). These last two hinder the detachment of the drug particles from the carrier surface. The success or failure of an interactive powder mixture as dry powder inhalation depends mainly on the magnitude of the adhesion forces, which fix the drug particles onto the carrier surface.
Obviously, a very high adhesion force is unwanted, because if the drug-carrier units cannot be split into their single components by the drag force, the whole drug-carrier units are swallowed. A balanced adhesion force promotes the split of the drug-carrier units into the micronized drug particles, which are inhaled, and the coarse carrier particles, which are swallowed. On the other hand, a too small adhesion force between drug and carrier particles might result in particle segregation and hence in higher variability in the content uniformity of dose. Also, drug particles are easier removed from the carrier particles during the sliding contact with the inhaler device walls, to which they tend to adhere firmly. Therefore, more drug is lost in the inhaler device.
The prior art teaches that the adhesion force in interactive powder mixtures for inhalation can be manipulated in several ways. First, the carrier particles can be chosen according to their median particle size, shape and surface roughness, which will result in large differences in the adhesion force for a defined mixing procedure and consequently in different aerosolisation properties.
A decrease in median particle size increases the adhesion force between drug and carrier particles. Larger adhesion forces are also found for irregular shaped or elongated carrier particles. This effect can be explained by an increase in friction during mixing. Surface roughness will either increase or decrease the adhesion force depending on the magnitude of the roughness. An increase in adhesion force will be found for extremely smooth carrier particle surfaces due to an increase in the true area of contact, or for very rough carrier particle surfaces, because here the wider spacing between the asperities allows mechanical entrapment of the micronized drug particles.
In typical DPI formulation, powders are pre-blended, which results in autoadhesion between the finer and coarse carrier particles. The finer carrier particles auto adhere, mainly due to mechanical entrapment in the grooves and clefts of the coarse carrier particle surfaces. The amount of finer carrier particles is thus physically removed, and the flow properties of the carrier powder are improved. Corrasion (a geological term implying filling of valleys) leads to a less wavy carrier particle surface, so that micronized drug particles are less likely to be mechanically trapped or embedded in the carrier particle surface. Corrasion also increases the micro-roughness of the carrier particle surfaces and hence reduces the adhesion force between drug and carrier particles due to a reduced true area of contact. However, it has been found that with respect to the adhesion forces and hence the dry powder inhalation function, corrasion is not always of advantage. A minimum surface roughness of the coarse carrier particles is required to allow the embedment of the finer carrier particles in the sense of corrasion. If the coarse carrier particle surface is relatively smooth, the finer carrier particles autoadhere in such a way, that the apparent macro-roughness of the carrier particle surface is increased, which in return offers more sites for the drug particles to be mechanically trapped. In this case, the drug particles can be removed from the carrier particle surfaces only as agglomerates with the finer carrier particles during re-suspension, and the drug deposition in the lungs depends on the size of these agglomerates.
The choice of the carrier material definitely influences the strength of the adhesion forces between drug and carrier particles. However, the place of application i.e. inhalation into the lungs limits this choice dramatically. To date, only lactose monohydrate and glucose are used as carrier materials in commercial dry powder inhalations. Glucose adsorbs moisture rapidly if stored in an environment of more than 55% relative humidity of the storage air. This will lead to strong capillary forces between drug and carrier particles. Lactose monohydrate has been claimed to reduce the vulnerability of the drug-carrier units to increased levels of humidity. However, adhesion force measurements between micronized drug and lactose monohydrate carrier particles after storage under different humidity conditions cast doubts on this opinion.
The use of an interactive powder mixture eases the handling of very low dose drugs for inhalations (for example salmeterol xinafoate: 50 microgram), so that they can be provided in single dose units such as foil blisters (such as in Advair Discus inhaler device) or capsules. Also, the increased homogeneity and reduced segregation of such mixtures is an advantage for the content.
Two common techniques to produce fine particles for DPIs are mechanical micronization and spray drying. A high-energy milling operation generates particles that are highly charged and thus very cohesive. To decrease cohesiveness, surfactants are used, for example, in wet milling. The milling process also introduces surface and crystallographic damage that affects powder stability.
The produced particles often contain irregular fragments that can form strong aggregates. In addition, multistep processing may cause significant losses of materials during powder production and variability of the product properties from batch to batch. Unlike milling, the spray-drying technique is a one-step continuous process that can directly produce pharmaceutical particles with a desired size. No surfactants or other solubilizing agents are needed in the process. However, the thermal history and drying rate of each particle is difficult to control due to the high flow rates needed in the process and limited controllable parameters. Consequently, the produced particles are usually amorphous and thus sensitive to temperature and humidity variations that may cause structural changes and sintering of the particles during storage of the powder.